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Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice.
J Gastroenterol Hepatol. 2009 Oct; 24(10):1658-68.JG

Abstract

BACKGROUND AND AIMS

We previously reported that steatohepatitis develops in obese, hypercholesterolemic, diabetic foz/foz mice fed a high-fat (HF) diet for 12 months. We now report earlier onset of steatohepatitis in relation to metabolic abnormalities, and clarify the roles of dietary fat and bodily lipid partitioning on steatosis severity, liver injury and inflammatory recruitment in this novel non-alcoholic steatohepatitis (NASH) model.

METHODS

Foz/foz (Alms1 mutant) and wild-type (WT) mice were fed a HF diet or chow, and metabolic characteristics and liver histology were studied at 2, 6, 12 and 24 weeks.

RESULTS

After 12 weeks HF-feeding, foz/foz mice were obese and diabetic with approximately 70% reduction in serum adiponectin. Hepatomegaly developed at this time, corresponding to a plateau in adipose expansion and increased adipose inflammation. Liver histology showed mild inflammation and hepatocyte ballooning as well as steatosis. By 24 weeks, HF-fed foz/foz mice developed severe steatohepatitis (marked steatosis, alanine aminotransferase elevation, ballooning, inflammation, fibrosis), whereas dietary and genetic controls showed only simple steatosis. While steatosis was associated with hepatic lipogenesis, indicated by increased fatty acid synthase activity, steatohepatitis was associated with significantly higher levels of CD36, indicating active fatty acid uptake, possibly under the influence of peroxisome proliferator-activated receptor-gamma.

CONCLUSION

In mice genetically predisposed to obesity and diabetes, HF feeding leads to restriction of adipose tissue for accommodation of excess energy, causing lipid partitioning into liver, and transformation of simple steatosis to fibrosing steatohepatitis. The way in which HF feeding 'saturates' adipose stores, decreases serum adiponectin and causes hepatic inflammation in steatohepatitis may provide clues to pathogenesis of NASH in metabolic syndrome.

Authors+Show Affiliations

Liver Research Group, ANU Medical School, Canberra Hospital, Garran, Australian Capital Territory 2605, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19788606

Citation

Larter, Claire Z., et al. "Roles of Adipose Restriction and Metabolic Factors in Progression of Steatosis to Steatohepatitis in Obese, Diabetic Mice." Journal of Gastroenterology and Hepatology, vol. 24, no. 10, 2009, pp. 1658-68.
Larter CZ, Yeh MM, Van Rooyen DM, et al. Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice. J Gastroenterol Hepatol. 2009;24(10):1658-68.
Larter, C. Z., Yeh, M. M., Van Rooyen, D. M., Teoh, N. C., Brooling, J., Hou, J. Y., Williams, J., Clyne, M., Nolan, C. J., & Farrell, G. C. (2009). Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice. Journal of Gastroenterology and Hepatology, 24(10), 1658-68. https://doi.org/10.1111/j.1440-1746.2009.05996.x
Larter CZ, et al. Roles of Adipose Restriction and Metabolic Factors in Progression of Steatosis to Steatohepatitis in Obese, Diabetic Mice. J Gastroenterol Hepatol. 2009;24(10):1658-68. PubMed PMID: 19788606.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice. AU - Larter,Claire Z, AU - Yeh,Matthew M, AU - Van Rooyen,Derrick M, AU - Teoh,Narci C, AU - Brooling,John, AU - Hou,Jing Yun, AU - Williams,Jacqueline, AU - Clyne,Matthew, AU - Nolan,Christopher J, AU - Farrell,Geoffrey C, PY - 2009/10/1/entrez PY - 2009/10/1/pubmed PY - 2009/12/16/medline SP - 1658 EP - 68 JF - Journal of gastroenterology and hepatology JO - J. Gastroenterol. Hepatol. VL - 24 IS - 10 N2 - BACKGROUND AND AIMS: We previously reported that steatohepatitis develops in obese, hypercholesterolemic, diabetic foz/foz mice fed a high-fat (HF) diet for 12 months. We now report earlier onset of steatohepatitis in relation to metabolic abnormalities, and clarify the roles of dietary fat and bodily lipid partitioning on steatosis severity, liver injury and inflammatory recruitment in this novel non-alcoholic steatohepatitis (NASH) model. METHODS: Foz/foz (Alms1 mutant) and wild-type (WT) mice were fed a HF diet or chow, and metabolic characteristics and liver histology were studied at 2, 6, 12 and 24 weeks. RESULTS: After 12 weeks HF-feeding, foz/foz mice were obese and diabetic with approximately 70% reduction in serum adiponectin. Hepatomegaly developed at this time, corresponding to a plateau in adipose expansion and increased adipose inflammation. Liver histology showed mild inflammation and hepatocyte ballooning as well as steatosis. By 24 weeks, HF-fed foz/foz mice developed severe steatohepatitis (marked steatosis, alanine aminotransferase elevation, ballooning, inflammation, fibrosis), whereas dietary and genetic controls showed only simple steatosis. While steatosis was associated with hepatic lipogenesis, indicated by increased fatty acid synthase activity, steatohepatitis was associated with significantly higher levels of CD36, indicating active fatty acid uptake, possibly under the influence of peroxisome proliferator-activated receptor-gamma. CONCLUSION: In mice genetically predisposed to obesity and diabetes, HF feeding leads to restriction of adipose tissue for accommodation of excess energy, causing lipid partitioning into liver, and transformation of simple steatosis to fibrosing steatohepatitis. The way in which HF feeding 'saturates' adipose stores, decreases serum adiponectin and causes hepatic inflammation in steatohepatitis may provide clues to pathogenesis of NASH in metabolic syndrome. SN - 1440-1746 UR - https://www.unboundmedicine.com/medline/citation/19788606/Roles_of_adipose_restriction_and_metabolic_factors_in_progression_of_steatosis_to_steatohepatitis_in_obese_diabetic_mice_ L2 - https://doi.org/10.1111/j.1440-1746.2009.05996.x DB - PRIME DP - Unbound Medicine ER -